Methods and compositions for the prevention and treatment of atherosclerosis, restenosis and related disorders

ABSTRACT

Methods and compositions for the prevention and treatment of all forms of atherosclerosis are described. Administration of compounds such as thalidomide, its analogs, hydrolysis products, metabolites, derivatives and precursors as well as additional compounds capable of inhibiting tumor necrosis factor α (TNF-α) are used in the invention.  
     Also disclosed is the coating of prosthetic devices, such as stents, with the compounds of the invention for the prevention and/or treatment of restenosis.

1. INTRODUCTION

[0001] The invention is directed to methods and compositions for theprevention and treatment of all forms of atherosclerosis, includingatherosclerosis found in the cardiovascular and renal systems. Moreparticularly, the present invention relates to the prevention and orreduction of stenosis and restenosis by administration of compounds suchas thalidomide, its analogs, hydrolysis products, metabolites,derivatives and precursors of thalidomide. Compounds which may be usedin the methods and compositions of the invention typically are capableof inhibiting tumor necrosis factor α (TNF-α). In another embodiment,the present invention is directed to the coating of prosthetic deviceswith these compounds for use or implantation into a subject, preferablya human. Preferred prosthetic devices include, for example, stentscoated with the compounds for the prevention and/or treatment ofrestenosis.

2. BACKGROUND OF THE INVENTION

[0002] In 1994, there were almost 1 million deaths due to vasculardisease in the United States (twice as many as from cancer and 10 timesas many as from accidents). Vascular disease may affect the brain,heart, kidneys, other vital organs as well as the extremities.

[0003] The most common and serious vascular disease is atherosclerosis.Atherosclerosis is characterized by patchy subintimal thickening(atheromas) of the medium-sized arteries such as the coronary arteries,mesenteric arteries, renal arteries and carotid arteries and the largearteries such as the aorta.

[0004] Development of atherosclerotic lesions involves proliferation ofcellular constituents of the wall of blood vessels in response tochemical stimuli from platelets and monocytes derived from the blood.This proliferation of cells in the vessel wall can lead to narrowing ofthe lumen of the vessel. In addition, atherosclerotic plaques, the focallesions of atherosclerosis, can be sites of thrombus or clot formation,hemorrhage, or ulceration leading to interruption of the blood supply ofthe organ supplied by the affected blood vessel e.g., thrombus formationover an atherosclerotic plaque in a coronary artery can occlude thevessel; depriving a portion of the heart of its blood supply and thuscausing ischemic death or infarction of heart muscle. Atheroscleroticplaque consists of accumulated intracellular and extracellular lipids,smooth,muscle cells, connective tissue, and giycosaminglycans. Theearliest detectable lesion of atherosclerosis is the fatty streak(consisting of lipid-laden foam cells, which are macrophages that havemigrated as monocytes from the circulation into the subendothelial layerof the intima), which later evolves into the fibrous plaque (consistingof intimal smooth muscle cells surrounded by connective tissue andintracellular and extracellular lipids).

[0005] The death rate from coronary artery disease (“CAD”) issignificant, for example, the death rates among white men aged 25 to 34is about 1/10,000; at age 55 to 64, it is nearly 1/100. This agerelationship may be due to the time required for lesions to develop orto the duration of exposure to risk factors.

[0006] Atherosclerotic vessels are characterized by having reducedsystolic expansion and abnormally rapid wave propagation.Arteriosclerotic arteries of hypertensive persons also have reducedelasticity, which is further reduced when atherosclerosis develops.

[0007] Two main hypotheses have been proposed to explain thepathogenesis of atherosclerosis: the lipid hypothesis and the chronicendothelial injury hypothesis.

[0008] The lipid hypothesis postulates that an elevation in plasma LDLlevels results in penetration of LDL into the arterial wall, leading tolipid accumulation in smooth muscle cells and in macrophages (foamcells). LDL also augments smooth muscle cell hyperplasia and migrationinto the subintinal and intimal region in response to growth factors.LDL is modified or oxidized in this environment and is rendered moreatherogenic.

[0009] The chronic endothelial injury hypothesis postulates thatendothelial injury by various mechanisms produces loss of endothelium,adhesion of platelets to subendothelium, aggregation of platelets tosubendothelium, aggregation of platelets, chemotaxis of monocytes andT-cell lymphocytes, and release of the platelet-derived andmonocyte-derived growth factors that induce migration of smooth musclecells from the media into the intima, where they replicate, synthesizeconnective tissue and proteoglycans and form a fibrous plaque. Othercells (e.g., macrophages, endothelial cells, arterial smooth musclecells) also produce growth factors that can contribute to smooth musclehyperplasia and extracellular matrix production.

[0010] Atherosclerotic plaque generally grow slowly and over time mayproduce a severe stenosis (a narrowing of the diameter of the artery) ormay progress to total arterial occlusion. With time, the plaque becomescalcified. Some plaques are stable, but others, especially those rich inlipids and inflammatory cells (e.g.,macrophages) and covered by a thinfibrous cap, may undergo spontaneous fissure or rupture, exposing theplaque contents to flowing blood. These plaques are deemed to beunstable or vulnerable and are more closely associated to the onset ofan acute ischemic event. The ruptured plaque stimulates thrombosis; thethrombi may embolize, rapidly occlude the lumen to precipitate heartattack or an acute ischemic syndrome, or gradually become incorporatedinto the plaque, contributing to its stepwise growth.

[0011] Atherosclerosis is characteristically silent until criticalstenosis, thrombosis, aneurysm, or embolus supervenes. Initially,symptoms and signs reflect an inability of blood flow to the affectedtissue to increase with demand (e.g., angina or exertion, intermittentclaudication). Symptoms and signs commonly develop gradually as theatheroma slowly encroaches on the vessel lumen. However, when a majorartery is acutely occluded, the results can be serious, such as, forexample, infarction of heart muscle as described above.

[0012] Traditional therapy for prevention or inhibition ofcardiovascular and cerebrovascular complications of atherosclerosis arereversing, to the extent possible, the risk factors associated withatherosclerosis such as cigarette smoking, obesity, abnormal serumlevels (LDL cholesterol levels), hypertension, diabetes mellitus,hyperhomocysteinemia and possibly C pneumoniae, infection. Hencetreatment to date, is generally directed to the complications ofatherosclerosis including angina pectoris, myocardial infarction,arrhythmias, heart failure, kidney failure, ischemic stroke, andperipheral arterial occlusion.

[0013] Further, vascular intervention, including angioplasty, stenting,atherectomy and grafting is often complicated by endothelial and smoothmuscle cell proliferation resulting in restenosis or re-clogging of theartery. This may be due to endothelial cell injury caused by thetreatment itself. Treatment of restenosis often involve a secondangioplasty or bypass surgery. The drawbacks of such treatment areobvious including the risk of repeat restenosis.

[0014] For example, angioplasty involves insertion of a balloon-tippedcatheter into an artery at the site of a partially obstructiveatherosclerotic lesion. Inflation of the balloon is intended to rupturethe intima and media and dilate the obstruction. About 20 to 30% ofobstructions reocclude in just a few days or weeks. Eltchaninoff et al.,Balloon Angioplasty For In-Stent Restenosis, 1998, J. Am Coll. Cardiol.,32(4): 980-984. Use of stents reduces the reocclusion rate, however asignificant percentage continue to result in restenosis. The rate ofstenosis after angioplasty is dependent upon a number of factorsincluding the length of the plaque. Stenosis rates vary from 10% to 35%depending the risk factors present. Further, repeat angiography one yearlater reveals an apparently normal lumen in only about 30% of vesselsundergoing the procedure.

[0015] In terms of the biological mechanism and characteristics leadingto restenosis, accumulation of extracellular matrix containing collagenand proteoglycans in association with smooth muscle cells characterizesboth the atheroma and the arterial hyperplastic lesion that lead torestenosis after balloon injury or clinical angioplasty. Some of thedelay in luminal narrowing with respect to smooth muscle cellproliferation may result from the continuing elaboration of matrixmaterials by neointimal smooth muscle cells. Various mediators may altermatrix synthesis by smooth muscle cells in vivo. A “cascade mechanism”has been proposed for restenosis. In this model, an injurious stimulusinduces expression of growth-stimulatory cytokines such as interleukin 1and tumor necrosis factor. Libby et al., Cascade Model of Restenosis1992, Circulation 86(6): III-47-III52.

[0016] More specifically, the acute local thrombosis, blood coagulationand/or mechanical injury appear to activate cyto gene expression bymacrophages and/or smooth muscle cells within the plaque. This acutecytokine expression evokes secondary, self-sustaining and continuingautocrine and paracrine growth factor and cytokine expression bylesional cells including leukocytes. For example, both vascularendothelial and smooth muscle cells can express genes encoding bothisoforms of the multipotent cytokine IL-1. Smooth muscle cells can alsoexpress the gene encoding TNF-α. Activated endothelial cells and smoothmuscle cells both elaborate the B and T cell activator IL-6. IL-6accounts for almost 4% of the newly synthesized proteins secreted bysmooth muscle cells stimulated by IL-1. Human vascular wall cells alsoproduce the monocyte chemoattractant and activator monocytechemoattractant protein-1 (MCP-1)/JE (also known as macrophagechemoattractant and activating factor) and the monocyte differentiationand activating factor M-CSF (a macrophage colony stimulating factor).

[0017] Various therapies have been attempted to treat or preventrestenosis. For example, it has been reported that, since oxidizingmetabolites may induce chain reactions that may lead to restenosis,multivitamins having antioxidant properties (30,000 IU of beta carotene,500 mg of vitamin C and 700 IU of vitamin E) and/or probucol (500 mg)were studied. They were administered twice daily for four weeks priorand six months after angioplasty, Tardif et al., N. Engl. J. Med.:337(6): 365-72 (1997). The antioxidant vitamins alone had no effect.Probucol did reduce the rate of restenosis after angioplasty by almost50%. However, probucol has removed from the U.S. market for reducing HDLcholesterol levels, and causing heart rhythm disturbances which mightlead to dangerous arrhythmias.

[0018] Intracoronary irradiation during angioplasty and stentimplantation to reduce the instances of restenosis have likewise beenstudied. Limitations include, for example, handling stents filled withradioactive liquid (Re 188-radioactive rhenium). Further, studies showthat this strategy may need to be tailored to stent design for properdistribution for the absorption and scattering of beta emitters. Amolset al., (1998) Circulation, 98.2024-2029.

[0019] Clearly, there remains a great need for therapies directed to theprevention and treatment of atherosclerosis, restenosis and relateddisorders.

3. SUMMARY OF THE INVENTION

[0020] The present invention includes methods and compositions for thetreatment or prevention of atherosclerosis, including diseases of thecardiovascular and renal systems, and in particular, the treatment orprevention of restenosis after vascular intervention such asangioplasty. One embodiment of the present invention includes theadministration of compounds including thalidomide, its analogs, itshydrolysis products, its metabolites, its derivatives or precursors ofthalidomide to treat or prevent atherosclerosis or the causes thereof,including stenosis. Compounds used in the invention typically exhibitTNF-α inhibitory activity. Administration as used in the inventionincludes oral, ophthalmic, (including intravitreal or intracameral),topical, mucosal (including buccal, rectal, vaginal, nasal andsublingual), transdermal or parenteral (including subcutaneous,intramuscular, intravenous, bolus injection, intradermal, intratracheal,and epidural) administration.

[0021] In another embodiment, the present invention relates to aprosthetic device suitable,for use or implantation into a subject,preferably a human. The device is coated with a composition containingthe compounds of the invention. The device is preferably a stent. Theformulated materials used in accordance with the present inventioncomprise thalidomide, its analogs and other TNF-α inhibitors. Thesecompositions are biocompatible.

[0022] Finally, the invention includes the combined use of a prophylaticor therapeutic administration of a compound of the invention inconjunction with the use of a stent coated with a compound of theinvention during surgery or implantation.

4. DETAILED DESCRIPTION OF THE INVENTION

[0023] The present invention includes methods and compositions for thetreatment or prevention of atherosclerosis, including diseases of thecardiovascular and renal systems, and in particular, the treatment orprevention of restenosis after vascular intervention such asangioplasty. One embodiment of the present invention includes theadministration of thalidomide or analogs, hydrolysis products,metabolites and precursors of thalidomide.

[0024] In 1953, N-phthaloyl-α-aminoglutarimide, commonly known asthalidomide, was discovered. Thalidomide was thought to be free from thedangerous side effects associated with barbiturates and was marketed inthe late 1950's as a sedative. The notoriety of thalidomide is basedupon its significant teratogenic effects discovered upon itsadministration to pregnant woman for morning sickness outside the UnitedStates (thalidomide was not approved in the United States due topossible peripheral neuropathic side effects not associated with itsteratogenic effects). In spite of thalidomide's tragic start as atherapeutic, thalidomide has been extensively studied and found toposses a number of therapeutic properties.

[0025] Thalidomide's anti-inflammatory effects were first noted as earlyas 1965. Skeskin J. Clin. Pharmacol. Ther. 6:303 (1965). Morespecifically, thalidomide was found to be extremely effective for thetreatment of erythema nodosum leprosum (ENL), an acute inflammatorymanifestation of lepromatous leprosy. More recently, thalidomide wasfound to exert immunomodulatory and anti-inflammatory effects in avariety of disease states, including graft-versus-host disease followingbone marrow transplantation, rheumatoid artliritis, inflammatory boweldisease (IBD), cachexia in AIDS, and opportunic infections in AIDS. Instudies to define the physiological targets of thalidomide, the drug wasfound to have a wide variety of biological activities exclusive of itssedative effect including neurotoxicity, teratogenicity, suppression ofTNF-α production by monocytes/macrophages and the accompanyinginflammatory toxicities associated with high levels of TNF-α, andinhibition of angiogenesis and neovascularization.

[0026] Additionally, beneficial effects have been observed in a varietyof dermatological conditions, ulcerative colitis, Crohn's disease,Behζets's syndrome, systemic lupus erythematosis, rheumatoid arthritis,aphthous ulcers, and lupus. Recently published results demonstrated theanti-angiogenic properties of thalidomide in in vivo models. D'Amato etal., Thalidomide Is An Inhibitor Of Angiogenesis, 1994, PNAS, USA91:4082-4085. Further preclinical and clinical trials in treatment ofcancer and in AIDS related conditions are ongoing.

[0027] The present invention adds to the field of uses for thalidomideand its derivatives for therapies directed to atherosclerosis,restenosis and related disorders.

4.1 The Compounds of the Invention

[0028] The preferred compounds of the invention are thalidomide, as wellas analogs, hydrolysis products, metabolites, derivatives and precursorsof thalidomide. Some of these compounds may be teratogenic (and thusmust be used with the proper safeguards). However, it is to beunderstood that it is not necessary for a compound to have teratogenicactivity to be considered part of the present invention.

[0029] Compounds useful in the present invention may also typicallyexhibit TNF-α inhibitory activity. The compounds of the inventioninclude cyano and carboxy derivatives of substituted styrenes includingthose found in U.S. Pat. No. 5,929,117; the cyclic imides (particularlythose described-in Muller, Thalidomide: From tragedy to new drugdiscovery, Chemtech 27(1):21-25(1997) which is incorporated by referencein its entirety) found in U.S. Pat. No. 5,605,914; the cycloalkyl amidesand cycloalkyl nitrites of U.S. Pat. Nos. 5,728,844 and 5,728,845,respectively; the aryl amides (for example, an embodiment beingN-benzoyl-3-amino-3-(3′,4′-dimethoxyphenyl)propanamide) of U.S. Pat.Nos. 5,801,195 and 5,736,570; the1-oxo-2-(2,6-dioxo-3-fluoropiperidin-3yl) isoindolines and1,3-dioxo-2-(2,6-dioxo-3-fluoropiperidine-3-yl) isoindolines of U.S.Pat. No. 5,874,448; the tetra substituted2-(2,6-dioxopiperdin-3-yl)-1-oxoisoindolines of U.S. Pat. No. 5,798,368;the imide/amide ethers and alcohols (for example3-phthalimido-3-(3′,4′-dimethoxypheryl)propan-1-ol) of U.S. Pat. No.5,703,098 and the succinimides and maleimides (for example methyl3-(3′,4′,5′6′-petrahydrophthalimdo)-3-(3″,4″-dimethoxyphenyl)propionate)as found in U.S. Pat. No. 5,658,940; 1-Oxo and1,3dioxo-2-(2,6-dioxopiperidin-3yl) isoindolines as described inReexamined U.S. Pat. No. B 5,635,517 Certificate issued Jun. 29, 1999; aclass of non-polypeptide cyclic amides disclosed in U.S. Pat. Nos.5,698,579 and 5,877,200; imido and amido substituted alkanohydroxamicacids found in WO 99/06041 and substituted phenethylsulfones disclosedin pending U.S. application Ser. No. 09/183,049; thalidomide, as well asits analogs, its hydrolysis products, its metabolites and its precursorsof thalidomide such as those described in D'Amato, U.S. Pat. Nos.5,593,990, 5,629,327, and 5,874,448. Each of the above described UnitedStates patents and applications are incorporated by reference in theirentireties.

[0030] In one embodiment, the preferred compounds are thalidomide, aswell as its analogs, its hydrolysis products, its metabolites and itsprecursors of thalidomide such as those described in D'Amato, U.S. Pat.Nos. 5,593,990, 5,629,327, and 5,874,448 each of which is incorporatedby reference in their entirety, including but not limited to compoundshaving the following structures:

[0031] It should be understood that the epoxide can be attached at the6,1 site on the benzene ring, the 1,2 site, the 2,3 site 3,4 or the 4,5site.

[0032] The above epoxides can be hydrolized to the following compoundswhich are also useful in the present invention:

[0033] All of these compounds are contemplated as part of the presentinvention. Other preferred embodiments include 1-Oxo-and 1,3dioxo-2-(2,6-dioxopiperidin-3-yl) isoindolines substituted with amino inthe benzo ring as described in Reexamined U.S. Pat. No. B 5,635,517Certificate issued Jun. 29, 1999 for U.S. Pat. No. 5,635,517 originallyissued Jun. 3, 1997, which are incorporated in their entireties. Thesecompounds have the structure:

[0034] in which one of X and Y is C═O and the other of X and Y is C═O orCH₂

[0035] Particularly preferred compounds include:

[0036] 1-oxo-2-(2,6-dioxopiperidin-3-yl)-5-aminoisoindoline

[0037] 1-oxo-2-(2,6-dioxopiperidin-3-yl)-4-aminoisoindoline

[0038] 1-oxo-2-(2,6-dioxopiperidin-3-yl)-6-aminoisoindoline

[0039] 1-oxo-2-(2,6-dioxopiperidin-3-yl)-5-aminoisoindoline

[0040] 1,3dioxo-2-(2,6-dioxopiperidin-3-yl)-4-aminoisoindoline

[0041] 1,3dioxo-2-(2,6-dioxopiperidin-3-yl)-5-aminoisoindoline

[0042] Other preferred compounds include a class of non-polypeptidecyclic amides disclosed in U.S. Pat. Nos. 5,698,579 and 5,877,200 whichare incorporated herein in their entirety. Representative cyclic amidesinclude compounds of the formula:

[0043] in which:

[0044] n has a value of 1, 2, or 3;

[0045] R⁵ is o-phenylene, unsubstituted or substituted with 1 to 4substituents each selected independently from the group consisting ofnitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy,acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkylamino,dialkylamino, acylamino, alkyl of 1 to 10 carbon atoms, alkyl of 1 to 10carbon atoms, and halo;

[0046] R⁷ is (i) phenyl or phenyl substituted with one or moresubstituents each selected independently of the other from the groupconsisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy,carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkylof 1 to 10 carbon atoms, aloxy of 1 to 10 carbon atoms, and halo, (ii)benzyl unsubstituted or substituted with 1 to 3 substituents selectedfrom the group consisting of nitro, cyano, trifluoromethyl, carbothoxy,carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy,hydroxy, amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbonatoms, and halo, (iii) naphthyl, and (iv) benzyloxy;

[0047] R¹² is—OH, alkoxy of 1 to 12 carbon atoms, or

[0048] R⁸ is hydrogen or alkyl of 1 to 10 carbon atoms; and

[0049] R⁹ is hydrogen, alkyl of 1 to 10 carbon atoms, —COR¹⁰, or —SO₂R¹⁰in which

[0050] R¹⁰ is hydrogen, alkyl of 1 to 10 carbon atoms, or phenyl.

[0051] Specific preferred compounds of this class include but are notlimited to:

[0052] 3-phenyl-2-(1-oxoisoindolin-2-yl)propionic acid;

[0053] 3-phenyl-2-(1-oxoisoindolin-2-yl)propionamide;

[0054] 3-phenyl-3-(1-oxoisoindolin-2-yl)propionic acid;

[0055] 3-phenyl-3-(1-oxoisoindolin-2-yl)propionamide;

[0056] 3-(4-methoxyphenyl)-3-(1-oxisoindolin-yl)propionic acid;

[0057] 3-(4-methoxyphenyl)-3-(1-oxisoindolin-yl)propionamide;

[0058] 3-(3,4-dimethoxyphenyl)-3-(1-oxisoindolin-2-yl)propionic acid;

[0059] 3-(3,4-dimethoxyphenyl)-3-(1-oxisoindolin-2-yl)propionamide;

[0060] 3-(3,4-diethoxyphenyl)-3-(1-oxoisoindolin-yl)propionic acid;

[0061] methyl3-(1-oxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate;

[0062] 3-(1-oxoisoindolin-2-yl)-3-(3-ethoxy4-methoxyphenyl)propionicacid;

[0063] 3-(1-oxoisoindolin-2-yl)-3-(3-propoxy-4-methoxyphenyl)propionicacid;

[0064] 3-(1-oxoisoindolin-2-yl)-3-(3-butoxy4-methoxyphenyl)propionicacid;

[0065] 3-(1-oxoisoindolin-2-yl)-3-(3-propoxy4-methoxyphenyl)propionamide;

[0066] 3-(1-oxoisoindolin-2-yl)-3-(3-butoxy4-methoxyphenyl)propionamide;

[0067] methyl3-(1-oxoisoindolin-2-yl)-3-(3-butoxy-4-methoxyphenyl)propionate; and

[0068] methyl3-(1-oxoisoindolin-2-yl)-3-3-propoxy-4-methoxyphenyl)propionate.

[0069] Other preferred compounds for use in the invention include theimido and amido substituted alkanohydroxamic acids found in WO 99/06041,which is also incorporated by reference in its entirety, including:

[0070] wherein:

[0071] each of R¹ and R², when taken independently of each other, ishydrogen, lower alkyl, or R¹ and R², when taken together, together withthe depicted carbon atoms to which each is bound, is o-phenylene,o-naphthylene, or cyclohexene-1,2-diyl, unsubstituted or substitutedwith 1 to 4 substituents each selected independently from the groupconsisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy,carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino,alkylamino, dialkylamino, acylamino, alkyl of 1 to 10 carbon atoms,alkoxy of 1 to 10 carbon atoms, and halo;

[0072] R³ is phenyl substituted with from one to four substituentsselected from the group consisting of nitro, cyano, trifluoromethyl,carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy,carboxy, hydroxy, amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to10 carbon atoms, alkylthio of 1 to 10 carbon atoms, benzyloxy,cycloalkoxy of 3 to 6 carbon atoms, C₄-C₆-cycloalkylidenemethyl,C₃-C₁₀-alkylidenemethyl, indanyloxy, and halo; R⁴ is hydrogen, alkyl of1 to 6 carbon atoms, phenyl, or benzyl; R⁴ is hydrogen or alkyl of 1 to6 carbon atoms; R⁵ is —CH₂—, —CH₂—CO—,—SO₂—,—S—, or —NHCO—; and n has avalue of 0, 1, or 2; and

[0073] (b) the acid addition salts of said compounds which contain anitrogen atom capable of being protonated.

[0074] Particularly preferred compounds include but are not limited to:

[0075]3-(3-ethoxy-4-methoxyphenyl)-N-hydroxy-3-(1-oxoisoindolinyl)propionamide;

[0076] 3-(3thoxy4-methoxyphenyl)-N-methoxy-3-(1-oxoisoindolinyl)propionamide;

[0077]N-benzyloxy-3-(3-ethoxy4-methoxyphenyl)-3-phthalimidopropionamide;

[0078]N-benzyloxy-3-(3-ethoxy-4-methoxyphenyl)-3-(3-nitrophthalmido)propionamide;

[0079]N-benzyloxy-3-(3-ethoxy4-methoxyphenyl)-3-(1-oxoisoindolinyl)propionamide;

[0080] 3-(3-ethoxy-4-methoxyphenyl)-N-hydroxy-3-phthalimidopropionamide;

[0081] N-hydroxy-3-(3,4-dimethoxyphenyl)-3-phthalimidopropionamide;

[0082]3-(3-ethoxy-4-methoxyphenyl)-N-hydroxy-3-(3-nitrophthalimido)propionamide;

[0083]N-hydroxy-3-(3,4-dimethoxyphenyl)-3-(1-oxoisoindolinyl)propionamide;

[0084]3-(3-ethoxy-4-methoxyphenyl)-N-hydroxy-3-(4-methyl-phthalimido)propionamide;

[0085]3-(3-cyclopentyloxy-4-methoxyphenyl)-N-hydroxy-3-phthalimidopropionamide;

[0086] 3-(3-ethoxy4-methoxyphenyl)-N-hydroxy-3-(1,3-dioxo-2,3-dihydro-1H-benzo[f]isoindol-2-yl)propionamide;

[0087]N-hydroxy-3-{3-9(2-propoxy)-4-methoxyphenyl}-3-phthalimidopropionamide;

[0088]3-(3-ethoxy-4-methoxyphenyl)-3-(3,6-difluorophthalimido)-N-hydroxypropionamide;

[0089]3-(4-aminophthalimido)-3-(3-ethoxy-4-methoxyphenyl)-N-hydroxypropionamide;

[0090]3-(3-aminophthalimido)-3-(3-ethoxy4-methoxyphenyl)-N-hydroxypropionamide;

[0091]N-hydroxy-3-(3,4-dimethoxyphenyl)-3-(1-oxoisoindolinyl)propionamide;

[0092]3-(3-cyclopentyloxy-4-methoxyphenyl)-N-hydroxy-3-(1-oxoisoindolinyl)propionamide;and

[0093]N-benzyloxy-3-(3-ethoxy-4-methoxyphenyl)-3-(3-nitrophthalimido)propionamide.

[0094] Additional preferred compounds are inhibitors of nuclear factorκB (NFκB). NFκB has been implicated as a transcriptional activator in avariety of disease and inflammatory states and is thought to regulatecytoline levels including but not limited to TNF-α and also to be anactivator of HIV transcription (Dbaibo, et al., J. Biol. Chem. 1993,17762-66; Duh et al., Proc. Natl. Acad. Sci. 1989, 86, 5974-78;Bachelerie et al., Nature 1991, 350, 709-12; Suzuki et al., Biochem AndBiophys. Res. Comm. 1993, 193, 277-83). Such preferred compounds includethe substituted phenethylsulfones substituted to the phenyl group with aoxoisoindine group such as those found in pending U.S. patentapplication Ser. No. 09/183,049 and are as follows:

[0095] in which

[0096] the carbon atom designated * constitutes a center of chirality;

[0097] Y is C═O, CH2, SO₂, or CH₂C═O;

[0098] each of R¹, R², R³, and R⁴, independently of the others, ishydrogen, halo, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbonatoms, nitro, cyano, hydroxy, or —NR⁸R⁹; or any two of R¹, R², R³, andR⁴ on adjacent carbon atoms, together with the depicted phenylene ringare naphthylidene;

[0099] each of R⁵ and R⁶, independently of the other, is hydrogen, alkylof 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, cyano, orcycloalkoxy of up to 18 carbon atoms;

[0100] R⁷ is hydroxy, alkyl of 1 to 8 carbon atoms, phenyl, benzyl, orNR^(8′)R^(9′);

[0101] each of R⁸ and R⁹ taken independently of the other is hydrogen,alkyl of 1 to 8 carbon atoms, phenyl, or benzyl, or one of R⁸ and R⁹ ishydrogen and the other is —COR¹⁰ or —SO₂R¹⁰, or R⁸ and R⁹ taken togetherare tetramethylene, pentamethylene, hexamethylene, or —CH₂CH₂X¹CH₂CH₂—in which X¹ is —O—, —S— or —NH—; and

[0102] each of R^(8′) and R^(9′) taken independently of the other ishydrogen, alkyl of 1 to 8 carbon atoms, phenyl, or benzyl, or one ofR^(8′) and R^(9′) is hydrogen and the other is —COR^(10′) or—SO₂R^(10′), or R^(8′) and R^(9′) taken together are tetramethylene,pentamethylene, hexamethylene, or —CH₂CH₂X²CH₂CH₂— in which X² is —O—,—S—, or —NH—.

[0103] It will be appreciated that while for convenience the abovecompounds are identified as phenethylsulfones, they include sulfonamideswhen R⁷ is NR^(8′)R^(9′).

[0104] Preferred groups of such compounds are those in which Y is C═O;and Y is CH₂.

[0105] A further preferred group of such compounds are those in whicheach of R¹, R², R³, and R⁴ independently of the others,.is hydrogen,halo, methyl, ethyl, methoxy, ethoxy, nitro, cyano, hydroxy, or —NR⁸R⁹in which each of R⁸ and R⁹ taken independently of the other is hydrogenor methyl or one of R⁸ and R⁹ is hydrogen and the other is —COCH₃.

[0106] A further preferred group of such compounds are those in whichone of R¹, R², R³, and R⁴ is —NH₂ and the remaining of R¹, R², R³, andR⁴ are hydrogen.

[0107] A further preferred group of such compounds are those in whichone of R¹, R², R³, and R⁴is —NHCOCH₃ and the remaining of R¹, R², R³,and R⁴ are hydrogen.

[0108] A further preferred group of such compounds are those in whichone of R¹, R², R³, and R⁴ is —N(CH₃)₂ and the remaining of R¹, R², R³,and R⁴ are hydrogen.

[0109] A further preferred group of such compounds are those in whichone of R¹, R², R³, and R⁴ is methyl and the remaining of R¹, R², R³, andR⁴ are hydrogen.

[0110] A further preferred group of such compounds are those in whichone of R¹, R², R³, and R⁴ is fluoro and the remaining of R¹, R², R³, andR⁴ are hydrogen.

[0111] A further preferred group of such compounds are those in whicheach of R⁵ and R⁶, independently of the other, is hydrogen, methyl,ethyl, propyl, methoxy, ethoxy, propoxy, cyclopentoxy, or cyclohexoxy.

[0112] A further preferred group of such compounds are those in which R⁵is methoxy and R⁶ is monocycloalkoxy, polycycloalkoxy, andbenzocycloalkoxy.

[0113] A further preferred group of such compounds are those in which R⁵is methoxy and R⁶ is ethoxy.

[0114] A further preferred group of such compounds are those in which R⁷is hydroxy, methyl, ethyl, phenyl, benzyl, or NR^(8′)R^(9′) in whicheach of R^(8′) and R^(9′) taken independently of the other is hydrogenor methyl.

[0115] A further preferred group of such compounds are those in which R⁷is methyl, ethyl, phenyl, benzyl or NR^(8′R) ^(9′) in which each ofR^(8′) and R⁹ taken independently of the other is hydrogen or methyl.

[0116] A further preferred group of such compounds are those in which R⁷is methyl.

[0117] A further preferred group of such compounds are those in which R⁷is NR^(8′)R^(9′) in which each of R^(8′) and R^(9′) taken independentlyof the other is hydrogen or methyl. Specific preferred compounds of thisclass include but are not limited to:

[0118]2-[1(-3-ethoxy-4-methoxyphenyl)-2-methyl-sulfonylethyl]isoindolin-1-one,

[0119]2-[1-(-3-ethoxy-4-methoxyphenyl)-2-(N,N-dimethyl-aminosulfonyl)ethyl]isoindolin-1-one,

[0120]2-[1-(3-ethoxy-4-methoxyphenyl)-2-methyl-sulfonylethyl]isoindoline-1,3-dione,

[0121]2-[1-(3-ethoxy-4-methoxyphenyl)-2-methyl-sulfonylethyl]-5-nitro-isoindoline-1,3-dione,

[0122]2-[1-(3-ethoxy-4-methoxyphenyl)-2-methyl-sulfonylethyl]-4-nitroisoindol-1,3-dione,

[0123]2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-aminoisoindoline-1,3-dione,

[0124]2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-5-methylisoindoline-1,3-dione,

[0125]2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-5-acetamidoisoindoline-1,3-dione,

[0126]2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-dimethylaminoisondoline-1,3-dione,

[0127]2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-5-dimethylaminoisoindoline-1,3-dione,

[0128]2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]benzo[e]isoindoline-1,3-dione,

[0129]2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-methoxyisoindoline-1,3-dione,

[0130] 1-(3-cyclopentyloxy-4-methoxyphenyl)-2-methylsulfonylethyl-amine,

[0131]2-[1-(3-cyclopentyloxy-4-methoxyphenyl)-2-methylsulfonylethyl]isoindoline-1,3-dione,and

[0132]2-[1-(3-cyclopentyloxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-dimethylaminoisoindoline-1,3-dione.

[0133] Many of the compounds that are contemplated as part of thepresent invention can be enriched in optically active enantiomers of thecompounds specified above using standard resolution or asymetricsynthesis known in the art. Blaschke, for example, has reported that theS enantiomers may be disproportionately responsible for thedismelia-producing effect of thalidomide and its analogs. See, generallyBlaschke, Arzneimittelforschung 29:1640-1642 (1979). Procedures toobtain optically active preparations of the compounds of interest can befound in the literature. See, e.g., Shealy et al., Chem. Indus. 1030(1965); and Casini et al., Farmaco Ed. Sci. 19:563 (1964).

[0134] The present invention also pertains to the physiologicallyacceptable non-toxic acid addition salts of the compounds thereof Suchsalts include those derived from organic and inorganic acids or basesknow in the art: such acids include for example, hydrochloric acid,hydrobromic acid, phosphoric acid, sulfuric acid, methanesulphonic acid,acetic acid, tartaric acid, lactic acid, succinic acid, citric acid,malic acid, maleic acid, sorbic acid, aconitic acid, salicylic acid,phthalic acid, embolic acid, enanthic acid, and the like.

[0135] Compounds of the invention that are acidic in nature are capableof forming salts with various pharmaceutically acceptable bases. Thebases that can be used to prepare pharmaceutically acceptable baseaddition salts of such acidic compounds of the invention are those thatform non-toxic base addition salts, i.e., salts containingpharmacologically acceptable cations such as, but not limited to, alkalimetal or alkaline earth metal salts and the calcium, magnesium, sodiumor potassium salts in particular. Suitable organic bases include, butare not limited to, N,N-dibenzylethylenediamine, chloroprocaine,choline, diethanolamine, ethylenediamine, meglumaine(N-methylglucamine), lysine, and procaine.

[0136] Certain of these compounds, such as thalidomide are commerciallyavailable (Thalomid™, Celgene, Inc., Warren, N.J.). Other abovecompounds can be made by methods known in the art, including thosedisclosed in the patents cited above which are incorporated by referencein their entries.

[0137] Clearly, the most preferred compound of the invention isthalidomide.

[0138] 4.2 Compositions, Formulations, and Routes of Administration

[0139] The compounds described above can be provided as pharmaceuticallyacceptable formulations using formulation methods known to those ofordinary skill in the art. Administration as used in the inventionincludes those suitable for oral, ophthalmic, (including intravitreal orintracameral), topical, mucosal (including buccal, rectal, vaginal,nasal and sublingual), transdermal or parenteral (includingsubcutaneous, intramuscular, intravenous, bolus injection, intradermal,intratracheal, and epidural) administration. In addition thecombinations may be incorporated into biodegradable polymers allowingfor sustained release of the compound, the polymers being implanted inthe vicinity of where drug delivery is desired. Biodegradable polymersand their use are described, for example, in detail in Brem et al., J.Neurosurg. 74:441-446 (1991).

[0140] The formulations include those suitable for oral, rectal,ophthalmic, (including intravitreal or intracameral) nasal, topical(including buccal and sublingual), vaginal or parenteral (includingsubcutaneous, intramuscular, intravenous, intradermal, intratracheal,and epidural) administration. The formulations may conveniently bepresented in unit dosage form and may be prepared by conventionalpharmaceutical techniques. Such techniques include the step of bringinginto association the active ingredient and the pharmaceutical carrier(s)or excipient(s). In general, the formulations are prepared by uniformlyand intimately bringing into associate the active ingredient with liquidcarriers or finely divided solid carriers or both, and then, ifnecessary, shaping the product.

[0141] Formulations of the present invention suitable for oraladministration may be presented as discrete units such as capsules,cachets or tablets each containing a predetermined amount of the activeingredient; as a powder or granules; as a solution or a suspension in anaqueous liquid or a non-aqueous liquid; or as an oil-in-water liquidemulsion or a water-in-oil emulsion and as. a bolus, etc.

[0142] A tablet may be made by compression or molding, optionally withone or more accessory ingredients. Compressed tablets may be prepared bycompressing, in a suitable machine, the active ingredient in aflee-flowing form such as a powder or granules, optionally mixed with abinder, lubricant, inert diluent, preservative, surface active ordispersing agent. Molded tablets may be made by molding, in a suitablemachine, a mixture of the powdered compound moistened with an inertliquid diluent. The tablets may be optionally coated or scored and maybe formulated so as to provide a slow or controlled release of theactive ingredient therein.

[0143] Formulations suitable for topical administration in the mouthinclude lozenges comprising the ingredients in a flavored basis, usuallysucrose and acacia or tragacanth; pastilles comprising the activeingredient in an inert basis such as gelatin and glycerin, or sucroseand acacia; and mouthwashes comprising the ingredient to be administeredin a suitable liquid carrier.

[0144] Formulations suitable for topical administration to the skin maybe presented as ointments, creams, gels and pastes comprising theingredient to be administered in a pharmaceutical acceptable carrier. Apreferred topical delivery system is a transdermal patch containing theingredient to be administered.

[0145] Formulations for rectal administration may be presented as asuppository with a suitable base comprising, for example, cocoa butteror a salicylate.

[0146] Formulations suitable for nasal administration, wherein thecarrier is a solid, include a coarse powder having a particle size, forexample, in the range of 20 to 500 microns which is administered in themanner in which snuff is administered, i.e., by rapid inhalation throughthe nasal passage from a container of the powder held close up to thenose. Suitable formulations, wherein the carrier is a liquid, foradministration, as for example, a nasal spray or as nasal drops, includeaqueous or oily solutions of the active ingredient.

[0147] Formulations suitable for vaginal administration may be presentedas pessaries, tamports, creams, gels, pastes, foams or sprayformulations containing in addition to the active ingredient suchcarriers as are known in the art to be appropriate.

[0148] Formulations suitable for parenteral administration includeaqueous and non-aqueous sterile injection solutions which may containanti-oxidants, buffers, bacteriostats and solutes which render theformulation isotonic with the blood of the intended recipient; andaqueous and non-aqueous sterile suspensions which may include suspendingagents and thickening agents. The formulations may be presented inunit-dose or multi-dose containers, for example, sealed ampules andvials, and may be stored in a freeze-dried (lyophilized) conditionsrequiring only the addition of the sterile liquid carrier, for example,water for injections, immediately prior to use. Extemporaneous injectionsolutions and suspensions may be prepared from sterile powders, granulesand tablets of the kind previously described.

[0149] Preferred unit dosage formulations are those containing a dailydose or unit, daily sub-dose, as herein above recited, or an appropriatefraction thereof, of the administered ingredient.

[0150] It should be understood that in addition to the ingredients,particularly mentioned above, the formulations of the present inventionmay include other agents conventional in the art having regard to thetype of formulation in question, for example, those suitable for oraladministration may include flavoring agents.

[0151] Oral dosage forms include tablets, capsules, dragees, and similarshaped, compressed pharmaceutical forms containing from about 1 ng to300 mg of drug per unit dosage. Isotonic saline solutions can be usedfor parenteral administration which includes intramuscular, intrathecal,intravenous and intra-arterial routes of administration. Rectaladministration can be effected through the use of suppositoriesformulated from conventional carriers such as cocoa butter.

[0152] Pharmaceutical compositions thus comprise one or more compoundsdescribed above and are associated with at least one pharmaceuticallyacceptable carrier, diluent or excipient. In preparing suchcompositions, the active ingredients are usually mixed with or dilutedby an excipient or enclosed within such a carrier which can be in theform of a capsule or sachet. When the excipient serves as a diluent, itmay be a solid, semi-solid, or liquid material which acts as a vehicle,carrier, or medium for the active ingredient. Thus, the compositions canbe in the form of tablets, pills, powders, elixirs, suspensions,emulsions, solutions, syrups, soft and hard gelatin capsules,suppositories, sterile injectable solutions and sterile packagedpowders. Examples of suitable excipients, include but are not limited tolactose, dextrose, sucrose, sorbitol, mannitol, starch, gum acacia,calcium silicate, microcrystalline cellulose, polyvinlypyrrolidinone,cellulose, water, syrup, and methyl cellulose, the formulations canadditionally include lubricating agents such as talc, magnesium stearateand mineral oil, wetting agents, emulsifying and suspending agents,preserving agents such as methyl- and propylhydroxybenzoates, sweeteningagents or flavoring agents.

[0153] The compositions preferably are formulated in unit dosage form,meaning physically discrete units suitable as a unitary dosage, or apredetermined fraction-of a unitary dose to be administered in a singleor multiple dosage regimen to human subjects and other mammals, eachunit containing a predetermined quantity of active material calculatedto produce the desired therapeutic effect in association with a suitablepharmaceutical excipient. The compositions can be formulated so as toprovide an immediate, sustained or delayed release of active ingredientafter administration to the patient by employing procedures well knownin the art.

[0154] In additional to the common dosage forms set out above, thecompounds can also be administered by controlled release means ordelivery devices that are well known to those or ordinary skill in theart, such as those described in U.S. Pat. No. 3,845,770; 3,916,899;3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591,767;5,120,548; 5,073,543; 5,639,476; 5,354,556; and 5,733,566, thedisclosures of which are incorporated herein by reference. These dosageforms can be used to provide slow or controlled-release of one or moreactive ingredients using, for example, hydropropylmethyl cellulose,other polymer matrices, gels, permeable membranes, osmotic systems,multilayer coatings, microparticles, liposomes, or microspheres or acombination thereof to provide the desired release profile in varyingproportions. Suitable controlled-release formulations known to those ofordinary skill in the art, including those described herein, can bereadily selected for use with the pharmaceutical compositions of theinvention. The invention thus encompasses single unit dosage formssuitable for oral administration such as, but not limited to, tablets,capsules, gelcaps, and caplets that are adapted for controlled-release.

[0155] All controlled-release pharmaceutical products have a common goalof improving drug therapy over that achieved by their non-controlledcounterparts. Ideally, the use of an optimally designedcontrolled-release preparation in medical treatment is characterized bya minimum of drug substance being employed to cure or control thecondition in a minimum amount of time. Advantages of controlled-releaseformulations include extended activity of the drug. In addition,controlled-release formulations can be used to affect the time of onsetof action or other characteristics, such as blood levels of the drug,and thus can affect the occurrence of side effects.

[0156] Most controlled-release formulations are designed to initiallyrelease an amount of drug that promptly produces the desired therapeuticeffect, and gradually and continually release of other amounts of drugto maintain this level of therapeutic effect over an extended period oftime. In order to maintain this constant level of drug in the body, thedrug must be released from the dosage form at a rate that will replacethe amount of drug being metabolized and excreted from the body.Controlled-release of an active ingredient can be stimulated by variousinducers, including, but not limited to, pH, temperature, enzymes,water, or other physiological conditions or compounds.

[0157] 4.3 Therapies for Atherosclerosis and Related Conditions 4.3.1Treatment for the prevention or reduction of Atherosclerosis

[0158] Those at high risk, having for example, a number of the riskfactors described above in the background section, may be appropriatecandidates for the therapies of the invention.

[0159] The compounds may be used to inhibit or treat all forms ofconditions involving atherosclerosis. In a preferred embodiment theinvention includes a therapy to reduce or prevent the degree ofrestenosis after vascular intervention such as angioplasty, stenting,atherectomy and grafting. All forms of vascular intervention arecontemplated by the invention including diseases of the cardiovascularand renal system. The following chart provides a listing of the majorsystemic arteries that may be in need of treatment, all of which arecontemplated by the invention: TABLE I Major Systemic Arteries ArteryBody Areas Supplied Axillary Shoulder and axilla Brachial Upper armBrachiocephalic Head, neck, and arm Celiac Divides into left gastric,splenic, and hepatic arteries Common carotid Neck Common iliac Dividesinto external and internal iliac arteries Coronary Heart Deep femoralThigh Digital Fingers Dorsalis pedis Foot External carotid Neck andexternal head regions External iliac Femoral artery Femoral ThighGastric Stomach Hepatic Liver, gallbladder, pancreas, and duodenumInferior mesenteric Descending colon, rectum, and pelvic wall Internalcarotid Neck and internal head regions Internal iliac Rectum, urinarybladder, external genitalia, buttocks muscles, uterus and vagina Leftgastric Esophagus and stomach Middle sacral Sacrum Ovarian OvariesPalmar arch Hand Peroneal Calf Popliteal Knee Posterior tibial CalfPulmonary Lungs Radial Forearm Renal Kidney Splenic Stomach, pancreas,and spleen Subclavian Shoulder Superior mesenteric Pancreas, smallintestine, ascending and transverse colon Testicular Testes UlnarForearm

[0160] The optimal dosage to be administered will be readily determinedby those skilled in the art and will vary on the condition beingtreated, the particular TNF-α inhibitor and mode of administration.Other factors include the weight and condition of the human or animal.It is to be understood that the present invention has application forboth human and veterinary use. For oral administration to humans, adosage of between approximately 0.01 to 300 mg/kg/day.

[0161] In this embodiment, the compound or composition such as athalidomide composition is administered orally to a patient at risk forcomplications caused by atherosclerosis. Typically, those at riskinclude those having one or more of the following conditions: abnormalserum lipid levels, hypertension, cigarette smoking, diabetes mellitus,obesity, physical inactivity, hyperhomocysteinemia and chlamydiapneumoniae infection.

[0162] The compound is thus administered prophylactically to preventserious complications or to avoid the need for surgical intervention.

[0163]4.3.2 Treatment for the Prevention or Reduction of Restenosis

[0164] Macrophage appear to infiltrate restenotic lesions of coronaryarteries. For example, in one study macrophage areas, but neither smoothmuscle cell nor tissue factor areas, were significantly larger inprimary lesions that develop restenosis when compared to primary lesionsthat did not develop into restenosis after coronary atherectomy. Morenoet al., Macrophage Infiltration Predicts Restenosis After CoronaryIntervention in Patients with Unstable Angina, 1996, Circulation94(12):3098-3102.

[0165] Further, it has been suggested the level of macrophage colonystimulating factor (M-CSF) in the atherectomy tissue can indicate, orpredict the likelihood or degree of restenosis in post vascularintervention tissue. Takano et al., High levels of circulatingMacrophage Colony Stimulating Factor (M-CSF) Predict Restenosis AfterPrimary Angioplasty in Patients With Acute Myocardial Infraction, 1998Circulation, 98 (17, Supp): 4437.

[0166] Thus, the invention encompasses the use of the compounds of theinvention in patients having abnormally high levels of circulatingmacrophage colony stimulating factor (M-CSF) prior to vascularintervention. This treatment may avoid the need for or facilitatevascular intervention.

[0167] All forms of vascular intervention are contemplated by theinvention, including for example, renal angioplasty, percutaneouscoronary intervention (PCI), percutaneous transluminal coronaryangioplasty (PTCA); carotid percutaneous transluminal angioplasty (PTA);coronary by-pass grafting, angioplasty with stent implantation,peripheral percutaneous transluminal intervention of the iliac, femoralor popliteal arteries, surgical intervention using impregnatedartificial grafts and the like.

[0168] The magnitude of a therapeutic dose of the compound will varywith the severity of the condition being treated, the route ofadministration and the particular compound being administered.Additionally, the dose, and dose frequency will also vary according tothe age, body weight and general condition of the individual patient. Ingeneral, the administration will begin just prior to (˜12 hours) orduring the angioplasty and will typically continue for 4 to 12 weeks.The daily dose range of the compound administered orally is between 0.01to 300 mg/kg/day.

[0169] A dosage regime following angioplasty may be desired and may benecessary in the case of emergency vascular intervention. The dosagewould be similar to the pre-angioplasty dosage and would typically becompleted by about four to twelve weeks after the angioplasty. Thus, theinvention encompasses the treatment or prevention of restenosis inpatients after surgical intervention by the administration ofthalidomide or an analogue, metabolite or prodrug thereof.

[0170] 4.3.3 Coated Surgical Devices and Their Use in Surgery

[0171] In another embodiment, stent or other devices used in surgicalprocedures such as angioplasty are coated with thalidomide or anothercompound of the invention prior to use in the patient. This coating isdesigned to prevent restenosis and to otherwise benefit the patient.Systemic administration of thalidomide or another compound of theinvention after surgical intervention is also contemplated. It should berecognized that multilayer coatings or releaseable coatings are alsoencompassed. Releaseable coatings can directly deposit the activecompound e.g., thalidomide to the area at risk for restenosis.Alternatively, topicalinternal applications can be used.

[0172] In such an embodiment, the compounds of the invention may becoated or sealed on a prosthetic device which is suitable, e.g., forimplantation or other use in a subject, preferably a human. Examples ofsuch devices include, but are not limited to, all types of angioplastydevices including a stent or stent/graft, or a commercial syntheticvascular graft or a biologic vascular graft. Any stent, stent/graft ortissue engineered vascular graft (“tubes”) known in the art can becoated or sealed with the compounds of the present invention. The tubescan be metallic, or made from a biocompatible polymer, as well as abiodegradable polymer, such as, e.g., dacron polyester, poly(ethyleneterephthalate), polycarbonate, polymethylmethacrylate, polypropylene,polyalkylene oxalates, polyvinylchloride, polyurethanes, polysiloxanes,nylons, poly(dimethyl siloxane), polycyanoacrylates, polyphosphazenes,poly(amino acids), ethylene glycol I dimethacrylate, poly(methylmethacrylate), poly(2-hydroxyethyl methacrylate), poly(HEMA),polyhydroxyalkanoates, polytetrafluorethylene, polycarbonate,poly(glycolide-lactide) co-polymer, polylactic acid,poly(ε-caprolactone), poly(β-hydroxybutyrate), polydioxanone,poly(γ-ethyl glutamate), polyiminocarbonates, poly(ortho ester),polyanhydrides, alginate, dextran, chitin, cotton, polyglycolic acid,polyurethane, or derivatized versions thereof, i.e., polymers which havebeen modified to include, for example, attachment sites or cross-linkinggroups in which the polymers retain their structural integrity whileallowing for attachment of molecules, such as proteins, nucleic acids,and the like. The tubes can also be fabric-coated metal structures. Thetubes can also be made from combinations of metal and polymer. The tubescan be configured into any desired shape or conformation, such as, forexample, linear, tapered, bifurcated, etc., and may be prepared usingfiber technology, such as, e.g., crimped, woven, knitted, velour, doublevelour, with or without coils. The tubes can also be prepared bychemical extrusion, casting or molding using, for example, porousmaterials having linear or random pores that are circular or geometricin shape.

[0173] There are a variety of methods of manufacture available toprovide a prosthetic device, coated on at least one surface with asufficient amount of a compound of the present invention. The resultingcoating is preferably uniform and should be integral so that contactbetween the device surface(s) and the surrounding tissue is precluded.The compounds can be applied to the device by spraying at least onesurface of the device with the compounds in suspension, and allowing theapplied surface to dry. In another embodiment, the device can be dippedinto such a suspension, or by casting a suspension of the compounds overthe device, or by layering a device the a suspension of the compoundsover the device, or by impregnating a device with a suspension of thecompounds. The compounds may be applied to the inside surface of a tube.By applying the compounds on the inside of the tube, the compoundspromote proper reendothelialization of the lumen wall, promote woundhealing and prevent or inhibit one or more cardiovascular diseasestates, such as stenosis, restenosis or intimal and neointimalhyperplasias.

[0174] The particular amount of the preparation to be applied to thedevice can be easily determined empirically by comparing devices withdifferent amounts of the compound coated thereon and determining theefficacy of each by, for example, measuring. Also, one skilled in therelevant art and who is familiar with standard treatments would also bein a position to easily evaluate the efficacy of a device. Moreover,more than one coat of the compounds, either untreated or crosslinked,can be applied to a device. It is highly desirable to inspect the deviceonce coated to insure that there are no gaps or breaks present in thecoating.

[0175] Other methods of coating stents are well known in the art and arecontemplated by the invention, for example, U.S. Pat. No. 5,637,113describes coating stents with a polymer film, U.S. Pat. No. 5,837,313describes a drug release stent coating process; both of these patentsare incorporated herein in their entireties and for all purposes.

[0176] In a specific embodiment, a stent coated with the compounds thepresent invention, is provided. The compounds in or on the stent may becomplexed with a drug, such as an antibiotic agent or an antiviralagent, or mixtures thereof, in order to insure against graft rejection.Additional drugs which may be added to the coating includeantiplatelets, antithrombins, cytostatic and antiproliferative agentsfor example.

[0177] Compounds such as thalidomide may not need protection againstgraft rejection since thalidomide may have this effect itself.

[0178] The methods used for implanting the coated devices are analogousto those used for the implantation of such devices without the coating,and, of course, depend on the nature of the condition to be modified orcorrected. The surgery can be performed under either local or systemicanesthesia and, generally, involves an incision, spacing to accommodatethe implant, insertion, and suture.

[0179] The following examples will serve to further typify the nature ofthis invention but should not be construed as a limitation in the scopethereof, which scope is defined solely by the appended claims.

5. WORKING EXAMPLES

[0180] 5.1 Example

[0181] Tablets, each containing 50 mg of1-oxo-2-(2,6-dioxo-piperidin-3yl)-4- amino-isoindoline can be preparedin the following manner: Constituents (for 1000 tablets)1-oxo-2-(2,6-dioxo-piperidin-3yl)-4-amino-isoindoline 50.0 g  lactose50.7 g  wheat starch 7.5 g polyethylene glycol 6000 5.0 g talc 5.0 gmagnesium stearate 1.8 g demineralized water q.s.

[0182] The solid ingredients are first forced through a sieve of 0.6 mmmesh width. The active ingredient, lactose, talc, magnesium stearate andhalf of the starch then are mixed. The other half of the starch issuspended in 40 mL of water and this suspension is added to a boilingsolution of the polyethylene glycol in 100 mL of water. The resultingpaste is added to the pulverulent substances and the mixture isgranulated, if necessary with the addition of water. The granulate isdried overnight at 35° C., forced through a sieve of 1.2 mm mesh widthand compressed to form tablets of approximately 6 mm diameter which areconcave on both sides.

[0183] 5.2 Coating of a Stent

[0184] A 5% (w/w) solution of silicone solid in tetrahydrofuran (THF)(HPLC grade, Aldrich or EM Science) is prepared by adding the requiredTHF and a crosslinker agent into the silicone mixture. A separate 0.5%(w/w) solution of 1-oxo-2-(2,6-dioxo-piperidin-3yl)-4amino-isoindolinein THF is prepared by adding THF into a beaker containing1-oxo-2-(2,6-dioxo-piperidin-3yl)-4amino-isoindoline. The ratio ofW_(drug)/W_(silicone solid) is 0.1. The coating of the stent in anexpanded state is accomplished by spraying one cycle of siliconesolution, waiting for a short period of time (about 30 seconds), andspraying one cycle of solution, waiting for a short period of time(about 30 seconds), and then repeating the spraying sequence. The verylast spray cycle is silicone solution. For a coating thickness of 30microns, about 30 cycles each is applied. The number of spray cyclesused depends on the solution viscosity, the droplet size and the flowrate. The coated stent is then moved to a convection oven and cured at150° C. for 45 minutes.

What is claimed is:
 1. A method of preventing atherosclerosis in a mammal comprising administering to a mammal an effective amount of a TNF-α inhibitor selected from the group consisting of: cyano and carboxy derivatives of substituted styrenes; cyclic imides; cycloalkyl amides and cycloalkyl nitrites; aryl amides; 1-oxo-2-(2,6-dioxo-3-fluoropiperidin-3yl) isoindolines and 1,3-dioxo-2-(2,6-dioxo-3-fluoropiperidine-3-yl) isoindolines; tetra substituted 2-(2,6-dioxopiperdin-3-yl)-1-oxoisoindolines; imide/amide ethers and alcohols; succinimides and maleimides; 1-oxo-and 1,3 dioxo-2-(2,6-dioxopiperidin-3-yl) isoindolines substituted with amino in the benzo ring; imido and amido substituted alkanohydroxamic acids; substituted phenethylsulfones substituted to the phenyl group with an oxoisoindine group; 1-Oxo and 1,3 dioxo-2-(2,6-dioxopiperidin-3yl) isoindolines; non-polypeptide cyclic amides; imido and amido substituted alkanohydroxamic acids; and substituted phenethylsulfones.
 2. A method of preventing atherosclerosis in a mammal comprising administering to a mammal an effective amount of a TNF-α inhibitor selected from the group consisting of: 1-oxo-2-(2,6-dioxopiperidin-3-yl)-4-aminoisoindoline, 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)4-aminoisoindoline and 3-(3,4-dimethoxyphenyl)-3-(1-oxisoindolin-2-yl)propionamide.
 3. A method of preventing atherosclerosis in a mammal comprising administering to a mammal an effective amount of a TNF-α inhibitor selected from the group consisting of thalidomide, its analogs, its hydrolysis products, its metabolites and its precursors.
 4. A method of treating atherosclerosis in a mammal comprising administering to a mammal in need thereof an effective amount of a TNF-α inhibitor selected from the group consisting of: cyano and carboxy derivatives of substituted styrenes; cyclic imides; cycloalkyl amides and cycloalkyl nitrites; aryl amides; 1-oxo-2-(2,6-dioxo-3-fluoropiperidin-3yl) isoindolines and 1,3-dioxo-2-(2,6-dioxo-3-fluoropiperidine-3-yl) isoindolines; tetra substituted 2-(2,6-dioxopiperdin-3-yl)-1-oxoisoindolines; imidelamide ethers and alcohols; succinimides and maleimides; 1-oxo-and 1,3 dioxo-2-(2,6-dioxopiperidin-3-yl) isoindolines substituted with amino in the benzo ring; imido and amido substituted alkanohydroxamic acids; substituted phenethylsulfones substituted to the phenyl group with an oxoisoindine group; 1-Oxo and 1,3 dioxo-2-(2,6-dioxopiperidin-3 yl) isoindolines; non-polypeptide cyclic amides; imido and amido substituted alkanohydroxamic acids and substituted phenethylsulfones.
 5. A method of treating atherosclerosis in a mammal comprising administering to a mammal in need thereof an effective amount of a TNF-α inhibitor selected from the group consisting of: 1-oxo-2-(2,6-dioxopiperidin-3-yl)4-aminoisoindoline; 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-4-aminoisoindoline; and 3-(3,4-dimethoxyphenyl)-3-(1-oxisoindolin-2-yl)propionamide.
 6. A method of treating atherosclerosis in a mammal comprising administering to a mammal in need thereof an effective amount of a TNF-α inhibitor selected from the group consisting of thalidomide, its analogs, its hydrolysis products, its metabolites and its precursors.
 7. The method of claims 1, 2, 3, 4, 5, or 6 wherein the atherosclerosis is in the aorta, coronary artery, mesenteric arteries, or carotid arteries.
 8. The method of claims 1, 2, 3, 4, 5, or 6 wherein the atherosclerosis is in the renal arteries.
 9. The method of claims 1, 2, 3, 4, 5, or 6, wherein the mammal is a human.
 10. The method of claims 1, 2, 3 wherein the mammal is a human subject and is at risk for complications of atherosclerosis and has one or more of the following conditions: abnormal serum lipid levels, hypertension, cigarette smoking, diabetes mellitus, obesity, physical inactivity, hyperhomocysteinemia and chlamydia pneumoniae infection.
 11. The method of claim 10 wherein the subject and has not undergone surgical vascular intervention.
 12. The method of claims 1, 2, 3, 4, 5, or 6 wherein approximately 0.01 mg/kg to 300 mg/kg of body weight is administered per day.
 13. The method of claim 12 wherein approximately 0.1 mg/kg to 100 mg/kg of body weight is administered per day.
 14. The method of claim 13 wherein approximately 0.5 mg/kg to 50 mg/kg of body weight is administered per day.
 15. The method of claim 14 wherein approximately 1.0 mg/kg to 10 mg/kg of body weight is administered per day.
 16. The method of claim 1, 2, 3, 4, 5, or 6 wherein the method of administration is oral.
 17. A method of inhibiting or preventing restenosis in a mammal comprising administering to a mammal in need thereof an effective amount of a TNF-α inhibitor selected from the group consisting of: cyano and carboxy derivatives of substituted styrenes; cyclic imides; cycloalkyl amides and cycloalkyl nitrites; aryl amides; 1-oxo-2-(2,6-dioxo-3-fluoropiperidin-3yl) isoindolines and 1,3-dioxo-2-(2,6-dioxo-3-fluoropiperidine-3-yl) isoindolines; tetra substituted 2-(2,6-dioxopiperdin-3-yl)-1-oxoisoindolines; imide/amide ethers and alcohols (for example 3-Phthalimido-3-(3′,4′-dimethoxypheryl)propan-1-ol); succinimides and maleimides; 1-oxo- and 1,3 dioxo-2-(2,6-dioxopiperidin-3-yl) isoindolines substituted with amino in the benzo ring; imido and amido substituted alkanohydroxamic acids; substituted phenethylsulfones substituted to the phenyl group with an oxoisoindine group; 1-Oxo and 1,3 dioxo-2-(2,6-dioxopiperidin-3yl) isoindolines; non-polypeptide cyclic amides; imido and amido substituted alkanohydroxamic acids; and substituted phenethylsulfones.
 18. A method of inhibiting or preventing restenosis in a mammal comprising administering to a mammal in need thereof an effective amount of a drug selected from the group consisting of: 1-oxo-2-(2,6-dioxopiperidin-3-yl)-4-aminoisoindoline; 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-4-aminoisoindoline; and 3-(3,4-dimethoxyphenyl)-3-(1-oxisoindolin-2-yl)propionamide so that restenosis is prevented or reduced.
 19. A method of inhibiting or preventing restenosis in a mammal comprising administering to a mammal in need thereof an effective amount of a TNF-α inhibitor selected from the group consisting of thalidomide, its analogs, its hydrolysis products, its metabolites and its precursors so that restenosis is prevented or reduced.
 20. The method of claim 17 wherein approximately 0.01 mg/kg to 300 mg/kg of body weight administered per day.
 21. The method of claim 20 wherein approximately 0.1 mg/kg to 100 mg/kg of body weight is administered per day.
 22. The method of claim 21 wherein approximately 0.5 mg/kg to 50 mg/kg of body weight is administered per day.
 23. The method of claim 22 wherein approximately 1.0 mg/kg to 10 mg/kg of body weight is administered per day.
 24. The method of claims 17, 18 or 19 wherein the treatment begins prior to surgical intervention.
 25. The method of claim 24 wherein treatment begins prior to surgical intervention and is continued for about 4 to 12 weeks after the surgical intervention.
 26. The method of claim 24 wherein the treatment begins about 12 hours or less prior to scheduled intervention.
 27. The method of claim 25 wherein the treatment begins about 12 hours or less prior to scheduled intervention.
 28. The method of claim 24 wherein the surgical intervention is percutaneous coronary intervention, percutaneous transluminal coronary angioplasty, carotid percutaneous transluminal angioplasty coronary by-pass grafting or coronary angioplasty with stent implantation.
 29. The method of claim 24 wherein the surgical intervention is renal angioplasty, peripheral percutaneous transluminal intervention of the iliac, femoral or popliteal arteries or surgical intervention using impregnated artificial grafts.
 30. The method of claims 17, 18, or 19 wherein the surgical intervention is unscheduled and treatment begins at the time of surgery.
 31. The method of claims 17, 18, or 19 wherein the surgical intervention is unscheduled and treatment begins at the time of surgery and is discontinued about 4 to 12 weeks after the surgical intervention.
 32. A prosthetic device suitable for implantation or use in a mammal wherein said device is coated on at least one surface with a therapeutically effective amount of a TNF-α inhibitor selected from the group consisting of: cyano and carboxy derivatives of substituted styrenes; cyclic imides; cycloalkyl amides and cycloalkyl nitrites; aryl amides; 1-oxo-2-(2,6-dioxo-3-fluoropiperidin-3yl) isoindolines and 1,3-dioxo-2-(2,6-dioxo-3-fluoropiperidine-3-yl) isoindolines; tetra substituted 2-(2,6-dioxopiperdin-3-yl)-1-oxoisoindolines; imide/amide ethers and alcohols; succinimides and maleimides propionate; 1-oxo-and 1,3 dioxo-2-(2,6-dioxopiperidin-3-yl) isoindolines substituted with amino in the benzo ring; imido and amido substituted alkanohydroxamic acids; substituted phenethylsulfones substituted to the phenyl group with an oxoisoindine group; 1-Oxo and 1,3 dioxo-2-(2,6-dioxopiperidin-3 yl) isoindolines; non-polypeptide cyclic amides; imido and amido substituted alkanohydroxamic acids and substituted phenethylsulfones.
 33. A prosthetic device suitable for implantation or use in a mammal wherein said device is coated on at least one surface with a therapeutically effective amount of a composition comprising: 1-oxo-2-(2,6-dioxopiperidin-3-yl)4-aminoisoindoline; 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-4-aminoisoindoline; and 3-(3,4-dimethoxyphenyl)-3-(1-oxisoindolin-2-yl)propionamide so that restenosis is prevented or reduced.
 34. A prosthetic device suitable for implantation or use in a mammal wherein said device is coated on at least one surface with a therapeutically effective amount of thalidomide, its analogs, its hydrolysis products, its metabolites or its precursors.
 35. The method of claim 32, 33 or 34 wherein the coating comprises a composition containing a pharmaceutically acceptable carrier, said carrier suitable for coating a prosthetic device.
 36. The device according to claims 32, 33 or 34 in which the device is selected from the group consisting of a stent or stent/graft.
 37. The device according to claims 32, 33 or 34 in which the device is composed of a nonbiodegradable material.
 38. The device according to claim 37 in which the nonbiodegradable material is a polyamide, a polyester, a polystyrene, a polypropylene, a polyacrylate, a polyvinyl, a polycarbonate, a polytetrafluorethylene, a polymethylmethacrylate, a polyethylene, a poly(ethylene terephthalate), a polyalkylene oxalate, a polyurethane, a polysiloxane, a poly(dimethyl siloxane), a polycyanoacrylate, a polyphosphazene, a poly(amino acid), a ethylene glycol I dimethacrylate, a poly(methyl methacrylate), a poly(2-hydroxyethyl methacrylate), a poly(HEMA),or a polyhydroxyalkanoate compound.
 39. A method for the production of a prosthetic device coated with a composition comprising compounds which inhibit TNF-α selected from the group consisting of: cyano and carboxy derivatives of substituted styrenes; cyclic imides; cycloalkyl amides and cycloalkyl nitrites; aryl amides; 1-oxo-2-(2,6-dioxo-3-fluoropiperidin-3yl) isoindolines and 1,3-dioxo-2-(2,6-dioxo-3-fluoropiperidine-3-yl) isoindolines; tetra substituted 2-(2,6-dioxopiperdin-3-yl)-1-oxoisoindolines; imide/amide ethers and, alcohols; succinimides and maleimides propionate; 1-oxo-and 1,3 dioxo-2-2,6-dioxopiperidin-3-yl) isoindolines substituted with amino in the benzo ring; imido and amido substituted alkanohydroxamic acids; substituted phenethylsulfones substituted to the phenyl group with an oxoisoindine group; 1-Oxo and 1,3 dioxo-2-(2,6-dioxopiperidin-3 yl) isoindolines; non-polypeptide cyclic amides; imido and amido substituted alkanohydroxamic acids and substituted phenethylsulfones comprising dipping, spraying, casting, layering or impregnating the device with a suspension of the compounds.
 40. A method for the production of a prosthetic device coated with a composition comprising compounds which inhibit TNF-α selected from the group consisting of: 1-oxo-2-(2,6-dioxopiperidin-3-yl)-4-aminoisoindoline; 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)4-aminoisoindoline; and 3-(3,4-dimethoxyphenyl)-3-(1-oxisoindolin-2-yl)propionamide comprising dipping, spraying, casting, layering or impregnating the device with a suspension of the compounds.
 41. A method for the production of a prosthetic device coated with a composition comprising compounds which inhibit TNF-α selected from the group consisting of: thalidomide, its analogs, its hydrolysis products, its metabolites and its precursors comprising dipping, spraying, casting, layering or impregnating the device with a suspension of the compounds.
 42. The method according to claims 39, 40 or 41 in which the device is selected from the group consisting of a stent or stent/graft. 